Derivatives of octahydro-6, 10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic acid, their preparation process and their use in the preparation of therapeutically active compounds

ABSTRACT

A compound of the formula  
                 
 
     of SR configuration or a SR+SS wherein R is selected from the group consisting of hydrogen, alkyl of up to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms and the —NH 2  is free or protected useful as intermediates.

[0001] The present invention relates to new derivatives ofoctahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylicacid, their preparation process and their use in the preparation oftherapeutically active compounds.

[0002] A subject of the invention is the compounds of formula (I):

[0003] of SR configuration or in the form of an SR SS mixture, in whichR represents a hydrogen atom, an alkyl or aralkyl radical containing upto 18 carbon atoms, the amine function being able to be free orprotected.

[0004] R represents for example an H, methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl or tertbutyl radical, or a benzyl or naphthyl radical.When the amine function is protected, the protection can be carried outaccording to standard methods for the protection of amines.

[0005] A particular subject of the invention is the compoundscorresponding to formula (IA):

[0006] of SR configuration or in the form of an SR+SS mixture, in whichR retains its previous meaning and either R₁ represents

[0007] radical

[0008] Ra, Rb, Rc and Rd representing an alkyl or aryl radicalcontaining up to 18 carbon atoms, or a mono or polycyclic radicalcontaining one or more heteroatoms, X representing a hydrogen atom, analkyl radical containing up to 8 carbon atoms or an aryl radicalcontaining up to 14 carbon atoms, and R₂ represents a hydrogen atom,

[0009] or R₁ and R₂ form together a mono or polycyclic radicalcontaining one or more heteroatoms.

[0010] For example, in order to protect the amines, cyclic compounds canbe used, for example the

[0011] radicals, or also the

[0012] radical.

[0013] A more particular subject of the invention is the compounds offormula (IA) in which R₁ and R₂ together form a polycyclic radicalcontaining one or more heteroatoms and in particular the compoundscorresponding to formula (IA₁)

[0014] of SR configuration or in the form of an SR+SS mixture.

[0015] A particular subject of the invention is the compounds of formula(I) in which R represents a methyl radical, of SR configuration or inthe form of an SR+SS mixture.

[0016] A subject of the invention is also a process characterized inthat a compound of formula (II)

[0017] in which alk represents an alkyl radical containing up to 8carbon atoms and Hal represents a halogen atom, is subjected to theaction of a compound of formula (III):

[0018] in which Aryl represents an aryl radical containing up to 14carbon atoms, in order to obtain the compound of formula (IV):

[0019] which is subjected to the action of a basic agent, in order toobtain the compound of formula (V):

[0020] which is optionally subjected to the action of an alkylationagent in order to obtain the compound of formula (VI):

[0021] which is subjected to the action of a compound of formula (VII):

[0022] in which Hal₁ represents a halogen atom and Ar represents an arylor aralkyl radical containing up to 18 carbon atoms, R₁ and R₂ retainingthe same definition as previously, in order to obtain the compound offormula (VIII):

[0023] of SR configuration or in the form of an SR+SS mixture, which issubjected to the action of a hydrogenation agent in order to obtain thecompound of formula (IX):

[0024] of SR configuration or in the form of an SR+SS mixture, which issubjected to the action of a condensation agent in order to obtain thecorresponding compound of formula (IA), then if desired, theamine:-function is released in order to obtain the compound of formula(I) in which the amine function is free.

[0025] In a preferred embodiment:

[0026] Hal and Hal₁ represent a chlorine atom,

[0027] alk represents an alkyl radical containing up to 4 carbon atoms,

[0028] Aryl represents a phenyl or naphthyl radical,

[0029] aralkyl represents a benzyl radical,

[0030] the reaction between the compounds of formula (II) and formula(III) takes place in the presence of a base for example in the presenceof an alkaline carbonate such as potassium carbonate,

[0031] the basic agent which is reacted on the compound of formula (IV)is sodium or potassium hydroxide,

[0032] the alkylation agent which is reacted on the compound of formula(V) is an alcohol for example methanol,

[0033] the condensation between the compounds (VI) and (VII) is carriedout in the presence of a base such as pyridine, TEA, diisopropylamine,

[0034] the hydrogenation agent is for example hydrogen in the presenceof palladium on carbon, palladium dihydroxide in the presence of talc,rhodium in the presence of alumina, ruthenium on carbon, or in thepresence of Raney nickel,

[0035] the cyclization is carried out in the presence of SOCl₂ or PCl₅or activated esters or in the presence of dehydration agents such asPTSA,

[0036] the release of the amine can be carried out using hydrazine.

[0037] The products (IV), (VII), (VIII) and (IX) used during the processare new products and are in themselves a subject of the presentinvention.

[0038] A more particular subject of the invention is the products thepreparation of which is given hereafter in the experimental part and inparticular the racemic mixture.

[0039] A subject of the invention is also the use characterized in thata compound of formula (I) in the form of an SS,SR mixture, or in SRform, is subjected to the action of a deracemization agent of theasymmetric carbon carried by the ring with 6 members, in order to obtainthe compound of formula (Iopt)

[0040] in SS form, in which the amine function is free or protected andR retains its previous meaning.

[0041] A more particular subject of the invention is the use of thecompounds of formula (IA) defined above, for the preparation ofcompounds of formula (IAopt)

[0042] in the SS form, in which R, R₁ and R₂ retain their previousmeaning.

[0043] A more particular subject of the invention is the usecharacterized in that R represents a methyl radical, and that in whichthe amine function is protected in the form of phthalimido.

[0044] A more particular subject of the invention is the usecharacterized in that the deracemization agent is a base, moreespecially a strong base, for example an alkaline or alkaline-earthalcoholate such as sodium or potassium methylate, sodium or potassiumterbutylate, or a lithiated amine such as LDA.

[0045] A quite particular subject of the invention is the use describedhereafter in the experimental part for preparing:

[0046] (1s-cis)methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate.

[0047] The product of formula (I) of SS configuration in which R is aterbutyl radical and the amine is protected in the form of phthalimido,is described for example in the Patent EP 94095, this is an intermediateproduct in the synthesis of products having therapeutic properties.

[0048] The products of formula (I) generally can be used for thesynthesis of medicaments as indicated in the above patent.

[0049] The following examples illustrate the invention without limitingit.

EXAMPLE 1 (1S-cis)methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazeine-1-carboxylateand methyl(1R-trans)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate.

[0050] a) Preparation of 2,5-dibromopentanoic Acid

[0051] 39 ml of bromine is added to a mixture of 106 a off5-bromopentanoic acid and 1 ml of phosphorus tribromide. The reactionmixture is taken to 70˜80° C. for 16 hours 30 minutes. The reactionmedium is taken to 100° C. for 15 minutes, then allowed to return toambient temperature. 147 g of sought product is obtained.

[0052] b) Preparation of Ethyl 2,5-dibromopentanoate

[0053] 24.37 g of oxalyl chloride is added to a mixture containing 50 gof the product prepared in the preceding stage, 15 drops of DMF, and 300ml of methylene chloride. The reaction mixture is maintained underagitation, at ambient temperature, until the reaction is complete. Thereaction mixture is cooled down to 10° C. and 50 ml of ethyl alcohol isadded. The reaction medium is agitated for 30 minutes at 10° C., left toreturn to ambient temperature and agitated for 3 hours at ambienttemperature. After bringing to dryness, the sought product is obtained.

[0054] c) Preparation of Bis(phenylmethyl)1,2-hydrazinedicarboxylate

[0055] 1.5 litres of methanol and 25-g of hydrazine monohydrate at 80%are placed under nitrogen. The reaction medium is cooled down to 0° C.and 75 g of benzyl chloroformate is introduced at 0° C., then another 75g of benzyl chloroformate is introduced at the same time as a solutionof 93 g of sodium carbonate in 1100 ml of demineralized water. Thereaction mixture is maintained at 0° C. for 1 hour, followed byseparating and washing by displacement with a mixture of 100 ml ofmethanol and 100 ml of water, then washing by displacement with 500 mlof water at 0° C. After drying, 107.6 g of sought product is obtained.

[0056] d) Preparation of (S)3-ethyl-1,2-bis(phenylmethyl)-tetrahydro-1,2,3-pyridazinetricarboxylateand (R)3-ethyl-1,2-bis(phenylmethyl)-tetrahydro-1,2,3-pvridazinetricarboxylate

[0057] A suspension of 12.1 g of the product of ethyl2,5-dibromopentanoate and 50 cm³ of diglyme is introduced at 20˜25° C.into a suspension containing 10.42 g of bis(phenylmethyl)1,2-hydrazinedicarboxylate, 65 ml of diglyme and 8.26 g of potassiumcarbonate.

[0058] The suspension obtained is heated at 90° C. Agitation ismaintained for 48 hours, followed by cooling down to 20° C., pouringinto a solution containing 50 ml of 2N hydrochloric acid and 150 ml of amixture of water and ice, extracting with ethyl acetate, washing withwater, drying, filtering, rinsing with ethyl acetate and drying. Theproduct obtained is chromatographed on silica (elution heptane 40, AcOEt20) and 10.71 g of sought product is obtained.

[0059] e) Preparation of (S)1-(phenylmethyl)-tetrahydro-1,3(2H)-pyridazinedicarboxylate and (R)1-(phenylmethyl)-tetrahydro-1,3(2H)-pyridazinedicarboxylate

[0060] A solution containing 23.25 g of the product of the previousstage and 80 ml of ethanol is introduced into 338 ml of a solution ofsodium hydroxide in ethanol at 40 g per litre. Agitation is maintainedfor 5 hours 30 minutes and 57 ml of 2N soda is added. The reactionmixture is maintained under agitation for 30 hours. 141 ml of a solutionof 2N hydrochloric acid is added. 260 ml of the reaction mixture isdistilled under 80˜90 millibars. Extraction is carried out withdichloromethane, 20 ml of ethanol is added, followed by washing with amixture of water-normal solution of soda The aqueous phases areextracted with dichloromethane. The aqueous phases are combined,agitated and acidified with 135 ml of a 2N solution of hydrochloricacid. Extraction is carried out with dichloromethane, followed bywashing with water, drying, filtering, washing with methylene chloride,concentrating and drying. 146 ml of isopropyl ether is added, followedby agitation for 1 hour at 20° C., filtering, washing, concentrating anddrying. 11.41 g of sought product is obtained.

[0061] f) Preparation of (S) 3-methyl 1-(phenylmethyl)tetrahydro-1,3(2H)-pyridazinedicarboxylate and (R) 3-methyl1-(phenylmethyl) tetrahydro-1,3(2H)-pyridazinedicarboxylate

[0062] 220 ml of methanol and dehydrated paratoluene sulphonic acid(prepared from monohydrated PTSA. and 12 ml of dichioromethane) areadded to 11.05 g of the product prepared in the previous stage. Thesuspension obtained is maintained under agitation for 15 hours, heatedto 65° C. and maintained under agitation for 6 hours 30 minutes. Aftercooling down to 5° C., 5.5 ml of a 10% solution of sodium bicarbonate isadded, followed by concentrating under reduced pressure, taking up in amixture of 100 ml of dichloromethane and 100 ml of water. Agitation iscarried out, followed by decanting, washing the organic phase,extracting with dichloromethane, drying, filtering and concentrating.11.39 g of sought product is obtained.

[0063] g) Preparation of [3S-[2(R*),3R*]] 3-methyl 1-(phenylmethyl)2-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1,5-dioxo-5-(phenylmethoxy)pentyl]tetrahydro-1,3(2H) Pyridazine Dicarboxylate and [3R-[2(S*),3R*]]3-methyl 1-(phenylmethyl)2-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1,5-dioxo-5-(phenylmethoxy)pentyl] tetrahydro-1,3(2H) Pyridazine Dicarboxylate

[0064] A solution containing 11.01 g of the product prepared in theprevious stage and 50 ml of dichloromethane is introduced over 1 hour atabout 4° C. into a solution containing 19.88 g of phenylmethyl(S)-gamma-(chlorocarbonyl)-1,3-dihydro-1,3-dioxo-2H-isoindole-2-butanoateand 100 ml of dichloromethane. Agitation is carried out for 30 minutesat 4° C. and 4.15 ml of pyridine in 25 ml of dichloromethane isintroduced over 1 hour 30 minutes. Agitation is maintained for 15 hourswhile slowly allowing the reaction medium to return to ambienttemperature, followed by concentrating under reduced pressure, taking upin 200 ml of ethyl acetate, washing with a saturated solution of sodiumacid carbonate, agitating for 30 minutes, decanting, washing with asaturated solution of sodium acid carbonate, agitating and decanting.The reaction medium is washed with a solution containing 5 ml of anormal solution of hydrochloric acid and 25 ml of water, then with asaturated aqueous solution of sodium chloride and dried. Extraction iscarried out with ethyl acetate, followed by concentrating and drying.25.2 g of sought product is obtained.

[0065] h) Preparation of[6S-[(1(R*),6R*]]-1,3-dihydro-1,3-dioxo-gamma-[[6-(methoxycarbonyl)-tetrahydro-1(2H)-pyridazinyl]carbonyl]-2H-isoindole-2-butanoic Acid and[6R-[(1(S*),6R*]]-1,3-dihydro-1,3-dioxo-gamma-[[6-(methoxycarbonyl)-tetrahydro-1(2H)-pyridazinyl]carbonyl]-2H-isoindole-2-butanoicAcid

[0066] 20.23 g of the product of the previous stage, 250 ml of THF and3.03 g of palladium at 10% on carbon are introduced into a hydrogenapparatus. Hydrogen is passed through for 3 hours, another 3.03 g ofcatalyst is added. Hydrogenation is continued for 22 hours, followed byfiltering, washing with THF and evaporating. 25 ml of isopropanol isadded, followed by concentrating, driving off the THF, 15 ml ofisopropanol is added. A suspension is obtained to which 100 ml ofisopropyl ether is added, followed by agitation under nitrogen for 2hours, separating, washing with isopropyl ether with 5% isopropanol.After separating and drying, 9.5 g of sought product is obtained.

[0067] I) Preparation of (1S-cis)methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylateand (1R-trans)Methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate

[0068] A solution containing 1 ml of thionyl chloride and 40 ml ofmethylene chloride is added at 5° C. to a mixture containing 4.038 g ofthe product of the previous stage, 40 ml of dichloromethane and 0.4 mlof dimethylformamide. Agitation is carried out for 3 hours and 30minutes. The temperature is left to rise towards 20° C., followed byagitation for one hour 30 minutes and concentrating. A solutioncontaining 0.15 ml of thionyl chloride and 5 ml of methylene chloride isadded. The reaction mixture is maintained under agitation at about 20°C. for 16 hours, followed by cooling down to about 5° C. and 27 ml of asaturated aqueous solution of sodium acid carbonate is introduced.Agitation is carried out for 30 minutes, followed by decanting andwashing with a solution containing 10 ml of sodium bicarbonate and 40 mlof demineralized water. Agitation is carried out 3 minutes, followed bydecanting, extracting the aqueous phases with methylene chloride,drying, filtering, washing with methylene chloride and concentratingunder reduced pressure. 3.85 g of sought product is obtained.

[0069] Use of (1S-cis)Methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate

[0070] A solution containing 0.029 g of potassium terbutylate and 0.3 mlof DMF is introduced at a temperature of −45°/−48° C. over 1 hour 30minutes into a mixture containing 0.194 g of the product of Example 1,1.5 ml of dimethylformamide and 0.75 ml of terbutanol. The mixture ismaintained under agitation for 1 hour and after cooling down to −50° C.,0.4 g of powdered ammonium chloride is introduced. Agitation is carriedout for 10 minutes at −45° C., 1 ml of ammonium chloride at 20% is addedsuccessively twice whilst agitating again for 10 minutes after eachaddition. 2 ml of demineralized water is added, followed by extractingwith ethyl acetate, washing with demineralized water, decanting,concentrating and drying. 0.166 g of product is obtained. α_(D)=−75.3°(1% in methanol)

1) The compounds of formula (I):

of SR configuration or in the form of an SR+SS mixture, in which Rrepresents a hydrogen atom, an alkyl or aralkyl radical containing up to18 carbon atoms, the amine function being able to be free or protected.2) The compounds of formula (I) defined in claim 1, corresponding toformula (IA):

of SR configuration or in the form of an SR+SS mixture, in which R is asdefined in claim 1 and either R₁ represents a

radical Ra, Rb, Rc and Rd representing an alkyl or aryl radicalcontaining up to 18 carbon atoms, or a mono or polycyclic radicalcontaining one or more heteroatoms, X representing a hydrogen atom, analkyl radical containing up to 8 carbon atoms or an aryl radicalcontaining up to 14 carbon atoms, and R₂ represents a hydrogen atom, orR₁ and R₂ form together a mono or polycyclic radical containing one ormore heteroatoms. 3) The compounds of formula (IA) defined in claim 1 or2 in which R₁ and R₂ form together a polycyclic radical containing oneor more heteroatoms of SR configuration or in the form of an SR+SSmixture. 4) The compounds of formula (IA) defined in claim 3,corresponding to formula (IA₁):

of SR configuration or in the form of an SR+SS mixture. 5) The compoundsof formula (I) defined in any one of claims 1 to 4, in which Rrepresents a methyl radical. 6) The racemic mixture of the compounds offormula (I) defined in claim 1 the names of which follow: (1S-cis)methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylateand (1R-trans) methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2] diazepine-1-carboxylate.7) Process for the preparation of the compounds of formula (I) definedin any one of the previous claims, characterized in that a compound offormula (II):

in which alk represents an alkyl radical containing up to 8 carbon atomsand Hal represents a halogen atom, is subjected to the action of acompound of formula (III):

in which Aryl represents an aryl radical containing co to 14 carbonatoms, in order to obtain the compound of formula (IV):

which is subjected to the action of a basic agent, in order to obtainthe compound of formula (V):

which is optionally subjected to the action of an alkylation agent inorder to obtain the compound of formula (VI):

which is subjected to the action of a compound of formula (VII):

in which Hal₁ represents a halogen atom and Ar represents an aryl oraralkyl radical containing up to 18 carbon atoms, R₁ and R₂ retain thesame definition as in claim 2, in order to obtain the compound offormula (VIII):

of SR configuration or in the form of an SR+SS mixture, which issubjected to the action of a hydrogenation agent in order to obtain thecompound of formula (IX):

of SR configuration or in the form of an SR+SS mixture, which issubjected to the action of a condensation agent in order to obtain thecorresponding compound of formula (IA), then if desired, the aminefunction is released in order to obtain the compound of formula (I) inwhich the amine function is free. 8) As new chemical products, thecompounds of formulae (IV), (VIII) and (IX) defined in claim
 7. 9) Useof the compounds of formula (I) defined in any one of claims 1 to 6, inthe form of SS,SR mixtures or in SR form, characterized in that acompound of formula (I) is subjected to the action of a deracemizationagent of the asymmetric carbon carried by the ring with 6 members, inorder to obtain the compound of formula (Iopt):

in SS form, in which the amine function is free or protected and R is asdefined in claim
 1. 10) Use of the compounds of formula (IA) defined inany one of claims 2 to 6, for the preparation of the compounds offormula (IAopt):

in SS form, in which R, R₁ and R₂ retain the same definition as in claim2. 11) Use according to claim 9 or 10, characterized in that Rrepresents a methyl radical. 12) Use according to claim 9, 10 or 11,characterized in that the amine function is protected in the form ofphthalimido. 13) Use according to any one of claims 9 to 12,characterized in that the deracemization agent is a base. 14) Useaccording to claim 13, characterized in that the strong base is analkaline or alkaline-earth alcoholate or a lithiated amine. 15) Useaccording to any one of claims 10 to 14, characterized in that thestarting product is the racemic mixture according to claim 6 and theprepared product is: (1s-cis)methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-methylcarboxylate.